1Department of Surgery, Penn State College of Medicine, Hershey, Pennsylvania2Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania; and 3Department of Nutritional Sciences, Penn State University, University Park, Pennsylvania

Abstract

Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery (day 10). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at day 10. During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bε but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser555-phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2α and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis.

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